Department of General Surgery Medical Academy named after S.I. Georgievskiy, The Federal State Autonomous Educational Establishment of Higher Education “Crimean Federal University named after V.I. Vernadsky” Ministry of Education and Science of the Russian Federation

For the 3rd year students The text of the lectures and the minimum amount of knowledge necessary for a understanding of the subject material.

Topic: venous diseases

Authors: prof.Mikhailychenko V.Yu, Starykh A.A.

2015

Anatomy The peripheral venous system functions both as a reservoir to hold extra blood and as a conduit to return blood from the periphery to the heart and lungs. Unlike arteries, which possess 3 well- defined layers (a thin intima, a well-developed muscular media, and a fibrous adventitia), most veins are composed of a single tissue layer. Only the largest veins possess internal elastic membranes, and this layer is thin and unevenly distributed, providing little buttress against high internal pressures. The correct functioning of the venous system depends on a complex series of valves and pumps that are individually frail and prone to malfunction, yet the system as a whole performs remarkably well under extremely adverse conditions.

Primary collecting veins of the lower extremity are passive, thin-walled reservoirs that are tremendously distensible. Most are suprafascial, surrounded by loosely bound alveolar and fatty tissue that is easily displaced. These suprafascial collecting veins can dilate to accommodate large volumes of blood with little increase in back pressure so that the volume of blood sequestered within the venous system at any moment can vary by a factor of 2 or more without interfering with the normal function of the veins. Suprafascial collecting veins belong to the superficial venous system.

Outflow from collecting veins is via secondary conduit veins that have thicker walls and are less distensible. Most of these veins are subfascial and are surrounded by tissues that are dense and tightly bound. These subfascial veins belong to the deep venous system, through which all venous blood must eventually pass through on its way back to the right atrium of the heart. The lower limb deep venous system is typically thought of as 2 separate systems, one below the knee and one above.

The calf has 3 groups of paired deep veins: the anterior tibial veins, draining the dorsum of the foot; the posterior tibial veins, draining the sole of the foot; and the peroneal veins, draining the lateral aspect of the foot. Venous sinusoids within the calf muscle coalesce to form soleal and gastrocnemius intramuscular venous plexuses, which join the peroneal veins in the mid calf. These veins play an important role in the muscle pump function of the calf. Just below the knee, these tibial veins join to become the popliteal vein, which too can be paired on occasion.

Together, the calf’s muscles and deep vein system form a complex array of valves and pumps, often referred to as the “peripheral heart,” that functions to push blood upward from the feet against gravity. The calf-muscle pump is analogous to the common hand-pump bulb of a sphygmomanometer filling a blood pressure cuff. Before pumping has started, the pressure is neutral and equal everywhere throughout the system and the calf fills with blood, typically 100- 150 mL. When the calf contracts, the feeding perforator vein valves are forced closed and the outflow valves are forced open driving the blood proximally. When the calf is allowed to relax, the veins and sinusoids refill from the superficial venous system via perforating veins, and the outflow valve is then forced shut, preventing retrograde flow. With each “contraction,” 40-60% of the calf’s venous volume is driven proximally.

The deep veins of the thigh begin distally with the popliteal vein as it courses proximally behind the knee and then passes through the adductor canal, at which point its name changes to the femoral vein. (This important deep vein is sometimes incorrectly referred to as the superficial femoral vein in a misguided attempt to distinguish it from the profunda femoris, or deep femoral vein, a short, stubby vein that usually has its origin in terminal muscle tributaries within the deep muscles of the lateral thigh but may communicate with the popliteal vein in up to 10% of patients.

The term superficial femoral vein should never be used, because the femoral vein is in fact a deep vein and is not part of the superficial venous system. This incorrect term does not appear in any definitive anatomic atlas, yet it has come into common use in vascular laboratory practice. Confusion arising from use of the inappropriate name has been responsible for many cases of clinical mismanagement and death.) In theproximal thigh,the femoral vein and the deep femoral vein unite to form the common femoral vein, which passes upwards above the groin crease to become the iliac vein.

The external iliac vein is the continuation of the femoral vein as it passes upward behind the inguinal ligament. At the level of the sacroiliac joint, it unites with the hypogastric vein to form the common iliac vein. The left common iliac is longer than the right and more oblique in its course, passing behind the right common iliac artery. This anatomic asymmetry sometimes results in compression of the left common iliac vein by the right common iliac artery to produce May-Thurner syndrome, a left-sided iliac outflow obstruction with localized adventitial fibrosis and intimal proliferation, often with associated deep venous thrombosis. At the level of the fifth lumbar vertebra, the 2 common iliac veins come together at an acute angle to form the inferior vena cava.

superficial venous system

The deep venous system

Varicose veins are veins that have become enlarged and twisted. The term commonly refers to the veins on the leg, although varicose veins can occur elsewhere. Veins have pairs of leaflet valves to prevent blood from flowing backwards (retrograde flow or venous reflux). Leg muscles pump the veins to return blood to the heart (the skeletal-muscle pump), against the effects of gravity. When veins become varicose, the leaflets of the valves no longer meet properly, and the valves do not work (valvular incompetence). This allows blood to flow backwards and they enlarge even more. Varicose veins are most common in the superficial veins of the legs, which are subject to high pressure when standing. Besides being a cosmetic problem, varicose veins can be painful, especially when standing. Severe long-standing varicose veins can lead to leg swelling, venous eczema, skin thickening (lipodermatosclerosis) and ulceration. Life-threatening complications are uncommon, but varicose veins may be confused with deep vein thrombosis, which may be life-threatening. Non-surgical treatments include sclerotherapy, elastic stockings, elevating the legs, and exercise. The traditional surgical treatment has been vein stripping to remove the affected veins. Newer, less invasive treatments which seal the main leaking vein are available. Alternative techniques, such as ultrasound-guided foam sclerotherapy, radiofrequency ablation and endovenous laser treatment, are available as well. Because most of the blood in the legs is returned by the deep veins, the superficial veins, which return only about 10% of the total blood of the legs, can usually be removed or ablated without serious harm. Secondary varicose veins are those developing as collateral pathways, typically after stenosis or occlusion of the deep veins, a common sequel of extensive deep venous thrombosis (DVT). Treatment options are usually support stockings, occasionally sclerotherapy, and rarely limited surgery. Varicose veins are distinguished from reticular veins (blue veins) and telangiectasias (spider veins), which also involve valvular insufficiency, by the size and location of the veins. Many patients who suffer with varicose veins seek out the assistance of physicians who specialize in vein care or peripheral vascular disease. These physicians include vascular surgeons, phlebologists or interventional radiologists.

Signs and symptoms

 Aching, heavy legs (often worse at night and after exercise).  Appearance of spider veins (telangiectasia) in the affected leg.  Ankle swelling, especially in evening.  A brownish-yellow shiny skin discoloration near the affected veins.  Redness, dryness, and itchiness of areas of skin, termed stasis dermatitis or venous eczema, because of waste products building up in the leg.  Cramps may develop especially when making a sudden move as standing up.  Minor injuries to the area may bleed more than normal or take a long time to heal.  In some people the skin above the ankle may shrink (lipodermatosclerosis) because the fat underneath the skin becomes hard.  Restless legs syndrome appears to be a common overlapping clinical syndrome in patients with varicose veins and other chronic venous insufficiency.  Whitened, irregular scar-like patches can appear at the ankles. This is known as atrophie blanche. Complications Most varicose veins are reasonably benign, but severe varicosities can lead to major complications, due to the poor circulation through the affected limb.

 Pain, tenderness, heaviness, inability to walk or stand for long hours, thus hindering work  Skin conditions / Dermatitis which could predispose skin loss  Skin ulcers especially near the ankle, usually referred to as venous ulcers.  Development of carcinoma or sarcoma in longstanding venous ulcers. There have been over 100 reported cases of malignant transformation and the rate is reported as 0.4% to 1%.[7]  Severe bleeding from minor trauma, of particular concern in the elderly.  Blood clotting within affected veins. Termed superficial thrombophlebitis. These are frequently isolated to the superficial veins, but can extend into deep veins becoming a more serious problem.  Acute fat necrosis can occur, especially at the ankle of overweight patients with varicose veins. Females are more frequently affected than males.

Diagnosis Clinical tests Clinical tests that may be used include:

1) Trendelenburg test The Trendelenburg Test or Brodie-Trendelenburg test is a test which can be carried out as part of a physical examination to determine the competency of the valves in the superficial and deep veins of the legs in patients with varicose veins. With the patient in the supine position, the leg is flexed at the hip and raised above heart level. The veins will empty due to gravity or with the assistance of the examiner's hand squeezing blood towards the heart. A tourniquet is then applied around the upper thigh to compress the superficial veins but not too tight as to occlude the deeper veins. The leg is then lowered by asking the patient to stand. Normally the superficial saphenous vein will fill from below within 3 to 5 seconds as blood from the capillary beds reaches the veins; if the superficial veins fill more rapidly with the tourniquet in place there is valvular incompetence below the level of the tourniquet in the "deep" or "communicating" veins. After 20 seconds, if there has been no rapid filling, the tourniquet is released. If there is sudden filling at this point it indicates that the communicating veins are competent but the superficial veins are incompetent. The test is reported in two parts, the initial standing up of the patient (positive or negative based on rapid filling) and the second phase once the tourniquet is removed (positive or negative based upon rapid filling). For example, a possible outcome of the test would be negative-positive meaning that the initial phase of the test was negative indicating competence in the communicating veins and the second phase of the test was positive meaning that there is superficial vein incompetence. The test can be repeated with the tourniquet at different levels to further pinpoint the level of valvular incompetence:

 above the knee - to assess the mid-thigh perforators  below the knee - to assess incompetence between the short saphenous vein and the popliteal vein. Superficial veins of the leg normally empty into deep veins, however retrograde filling occurs when valves are incompetent, leading to varicose veins.

2) Perthe's test The Perthes test is a clinical test for assessing the patency of the deep femoral vein prior to varicose vein surgery. It is named after German surgeon Georg Perthes. The limb is elevated and an elastic bandage is applied firmly from the toes to the upper 1/3 of the thigh to obliterate the superficial veins only. With the bandage applied the patient is asked to walk for 5 minutes. If deep system is competent, the blood will go through and back to the heart. If the deep system is incompetent, the patient will feel pain in the leg.

3) Multiple tornique test However it should be noted that since the advent of Lower limbs venous ultrasonography, these tests are of limited or no value. Investigations Traditionally, varicose veins were only investigated using imaging techniques if there was a clinical suspicion of deep venous insufficiency, if they were recurrent, or if they involved the sapheno-popliteal junction. This practice is not now widely accepted. All patients with varicose veins should now be investigated using Duplex doppler ultrasound scanning. The results from a randomised controlled trial (RCT) on the follow up of patients with and without routine Duplex scan has shown a significant difference in recurrence rate and reoperation rate at 2 and 7 years of follow up. Stages

 C0 no visible or palpable signs of venous disease  C1 telangectasia or reticular veins  C2 varicose veins (sub-divided into C2A = Varicose veins with no symptoms i.e.: asymptomatic; C2S = Varicose veins with symptoms)  C3 edema  C4a skin changes due to venous disorders: pigmentation, eczema  C4b skin changes due to venous disorders: lipodermatosclerosis, atrophie blanche  C5 as C4 but with healed ulcers  C6 skin changes with active ulcers (venous insufficiency ulceration)

Causes

The illustration shows how a varicose vein forms in a leg. Figure A shows a normal vein with a working valve and normal blood flow. Figure B shows a varicose vein with a deformed valve, abnormal blood flow, and thin, stretched walls. The middle image shows where varicose veins might appear in a leg.

Comparison of healthy and varicose veins Varicose veins are more common in women than in men, and are linked with heredity. Other related factors are pregnancy, obesity, menopause, aging, prolonged standing, leg injury, and abdominal straining. Varicose veins are unlikely to be caused by crossing the legs or ankles. Less commonly, but not exceptionally, varicose veins can be due to other causes, as post phlebitic obstruction or incontinence, venous and arteriovenous malformations . More recent research has shown the importance of pelvic vein reflux (PVR) in the development of varicose veins. John Hobbs showed varicose veins in the legs could be due to ovarian vein reflux and John Lumley and his team showed recurrent varicose veins could be due to ovarian vein reflux. Mark Whiteley and his team reported that both ovarian and internal iliac vein reflux causes leg varicose veins and that this condition affects 14% of women with varicose veins or 20% of women who have had vaginal delivery and have leg varicose veins. In addition there is evidence that failing to look for, and treat, pelvic vein reflux can be a cause of recurrent varicose veins. There is increasing evidence for the role of incompetent Perforator veins (or "perforators") in the formation of varicose veins. and recurrent varicose veins. Varicose veins could also be caused by hyperhomocysteinemia in the body, which can degrade and inhibit the formation of the three main structural components of the artery: collagen,elastin and the proteoglycans. Homocysteine permanently degrades cysteine disulfide bridges and lysine amino acid residues in proteins, gradually affecting function and structure. Simply put, homocysteine is a 'corrosive' of long-living proteins, i.e. collagen or elastin, or lifelong proteins, i.e. fibrillin. These long-term effects are difficult to establish in clinical trials focusing on groups with existing artery decline.

Treatment Treatment can be either conservative or active. Active medical intervention can be divided into surgical and non-surgical treatments. Newer methods including endovenous laser treatment,radiofrequency ablation and foam sclerotherapy appear to work as well as surgery for varices of the greater saphenous vein. Conservative The National Institute for Health and Clinical Excellence (NICE) produced clinical guidelines in July 2013 recommending that all people with syptomatic varicose veins (C2S) and worse should be referred to a vascular service for treatment. Conservative treatments such as support stockings should not be used unless treatment was not possible. The symptoms of varicose veins can be controlled to an extent with the following:

 Elevating the legs often provides temporary symptomatic relief.  Advice about regular exercise sounds sensible but is not supported by any evidence.  The wearing of graduated compression stockings with variable pressure gradients (Class II or III) has been shown to correct the swelling, nutritional exchange, and improve the microcirculation in legs affected by varicose veins. They also often provide relief from the discomfort associated with this disease. Caution should be exercised in their use in patients with concurrent arterial disease.

 The wearing of intermittent pneumatic compression devices have been shown to reduce swelling and increase circulation  Diosmin/Hesperidine and other flavonoids.  Anti-inflammatory medication such as ibuprofen or aspirin can be used as part of treatment for superficial thrombophlebitis along with graduated compression hosiery – but there is a risk of intestinal bleeding. In extensive superficial thrombophlebitis, consideration should be given to anti-coagulation, thrombectomy or sclerotherapy of the involved vein.  Topical gel application, helps in managing symptoms related to varicose veins such as inflammation, pain, swelling, itching and dryness. Topical application-Noninvasive and has patient compliance. Surgical Several techniques have been performed for over a century, from the more invasive saphenous stripping, to less invasive procedures like ambulatory phlebectomy and CHIVA. Stripping Stripping consists of removal of all or part the saphenous vein (great/long or lesser/short) main trunk. The complications include deep vein thrombosis (5.3%), pulmonary embolism (0.06%), and wound complications including infection (2.2%). There is evidence for the Great Saphenous Vein growing back again after stripping. For traditional surgery, reported recurrence rates, which have been tracked for 10 years, range from 5–60%. In addition, since stripping removes the saphenous main trunks, they are no longer available for use as venous bypass grafts in the future (coronary or leg artery vital disease) Other Other surgical treatments are:

 Ambulatory phlebectomy  Vein ligation  Cryosurgery- A cryoprobe is passed down the long saphenous vein following

saphenofemoral ligation. Then the probe is cooled with NO2 or CO2 to a temperature of −85o. The vein freezes to the probe and can be retrogradely stripped after 5 second of freezing. It is a variant of Stripping. The only point of this technique is to avoid a distal incision to remove the stripper. Sclerotherapy

A commonly performed non-surgical treatment for varicose and "spider" leg veins is sclerotherapy in which medicine (sclerosant) is injected into the veins to make them shrink. The medicines that are commonly used as sclerosants are polidocanol (POL), sodium tetradecyl sulphate (STS), Sclerodex (Canada), Hypertonic Saline, Glycerin and Chromated Glycerin. STS (branded Fibrovein in Australia) and Polidocanol (branded Asclera in the United States, Aethoxysklerol in Australia) liquids can be mixed at varying concentrations of sclerosant and varying sclerosant/gas proportions, with air or CO2 or O2 to create foams. Foams may allow more veins to be treated per session with comparable efficacy. Their use in contrast to liquid sclerosant is still somewhat controversial. Sclerotherapy has been used in the treatment of varicose veins for over 150 years. Sclerotherapy is often used for telangiectasias (spider veins) and varicose veins that persist or recur after vein stripping. Sclerotherapy can also be performed using foamed sclerosants under ultrasound guidance to treat larger varicose veins, including the great saphenous and small saphenous veins. A study by Kanter and Thibault in 1996 reported a 76% success rate at 24 months in treating saphenofemoral junction and great saphenous vein incompetence with STS 3% solution. A Cochrane Collaboration review concluded sclerotherapy was better than surgery in the short term (1 year) for its treatment success, complication rate and cost, but surgery was better after 5 years, although the research is weak. A Health Technology Assessment found that sclerotherapy provided less benefit than surgery, but is likely to provide a small benefit in varicose veins without reflux. This Health Technology Assessment monograph includes reviews of the epidemiology, assessment, and treatment of varicose veins, as well as a study on clinical and cost effectiveness of surgery and sclerotherapy. Complications of sclerotherapy are rare but can include blood clots and ulceration. Anaphylactic reactions are "extraordinarily rare but can be life-threatening," and doctors should have resuscitation equipment ready. There has been one reported case of stroke after ultrasound guided sclerotherapy when an unusually large dose of sclerosant foam was injected. Endovenous thermal ablation The Australian Medical Services Advisory Committee (MSAC) in 2008 has determined that endovenous laser treatment/ablation (ELA) for varicose veins "appears to be more effective in the short term, and at least as effective overall, as the comparative procedure of junction ligation and vein stripping for the treatment of varicose veins." It also found in its assessment of available literature, that "occurrence rates of more severe complications such as DVT, nerve injury and paraesthesia, post-operative infections and haematomas, appears to be greater after ligation and stripping than after EVLT". Complications for ELA include minor skin burns (0.4%) and temporary paraesthesia (2.1%). The longest study of endovenous laser ablation is 39 months. Two prospective randomized trials found speedier recovery and fewer complications after radiofrequency ablation (ERA) compared to open surgery. Myers wrote that open surgery for small saphenous vein reflux is obsolete. Myers said these veins should be treated with endovenous techniques, citing high recurrence rates after surgical management, and risk of nerve damage up to 15%. In comparison, ERA has been shown to control 80% of cases of small saphenous vein reflux at 4 years, said Myers. Complications for ERA include burns, paraesthesia, clinical phlebitis, and slightly higher rates of deep vein thrombosis (0.57%) and pulmonary embolism (0.17%). One 3-year study compared ERA, with a recurrence rate of 33%, to open surgery, which had a recurrence rate of 23%. ELA and ERA require specialized training for doctors and expensive equipment. ELA is performed as an outpatient procedure and does not require the use of an operating theatre, nor does the patient need a general anaesthetic. Doctors must use high frequency ultrasound during the procedure to visualize the anatomical relationships between the saphenous structures. Some practitioners also perform phlebectomy or ultrasound guided sclerotherapy at the time of endovenous treatment. Follow-up treatment to smaller branch varicose veins is often needed in the weeks or months after the initial procedure.

Basic Mechanisms and Pathogenesis of Venous Thrombosis In 1856 Virchow proposed a triad of causes for venous thrombosis, postulating that stasis, changes in the vessel wall or changes in the blood could lead to thrombosis. We now know that abnormally high levels of some coagulation factors and defects in the natural anticoagulants contribute to thrombotic risk. Among these, factor V Leiden, which renders factor Va resistant to activated protein C, is the most prevalent with approximately 5% of the Caucasian population having this genetic alteration. These genetically controlled variants in coagulation factors work in concert with other risk factors, such as oral contraceptive use, to dramatically increase thrombotic risk. While these abnormalities in the blood coagulation proteins are associated with thrombotic disease propensity, they are less frequent contributors to thrombosis than age or cancer. Cancer increases thrombotic risk by producing tissue factor to initiate coagulation, by shedding procoagulant lipid microparticles or by impairing blood flow. Age is the strongest risk factor for thrombosis. Among possible reasons are fragility of the vessels potentially contributing to stasis, increased coagulation factor levels, impaired function of the venous valves, decreases in the efficacy of natural anticoagulants associated with the vessel wall, increased risk of immobilization and increased risk of severe infection.

A. Introduction

Virchow's triad predicts that the causes of thrombosis are changes in blood coaguability, changes in the vessel wall or stasis. More recent studies have provided a mechanistic understanding for some of the processes that cause each of these alterations to contribute to thrombosis. A combination of genetically manipulated mouse models and human epidemiology have revealed that a variety of genetic risk factors can contribute to venous thrombosis, but the site of the thrombotic risk varies depending on the defect

A modified version of Virchow's triad focusing on the findings that chronic low level inflammation has little impact on venous thrombosis (unlike arterial thrombosis), but that acute inflammation does increase venous thrombosis. One of the major concepts involved in either hemostasis or thrombosis is that the processes are localized. Simply increasing coagulation enzyme concentrations with or without added negatively charged phospholipid vesicles leads to thrombin generation, but this thrombin generation is widespread, usually leading to disseminated intravascular coagulation rather than either hemostasis or thrombosis.

A. Where does venous thrombosis begin and why?

Except in thrombosis associated with surgery, examination of the thrombus in the human veins seldom indicates evidence of injury, raising the question of how venous thrombosis is initiated. Venous thrombosis is believed to begin at the venous valves. These valves play a major role in helping with blood circulation in the legs. They are also areas where stasis and hypoxia may occur. Direct evidence from autopsy studies and phlebography have established the venous valvular sinus as a frequent location of thrombosis initiation. This phenomenon has been attributed to stasis, one of the components of Virchow's triad. Contrast media lingers in valve sinuses taking an average of 27 min to clear post-venography. Valvular sinus stasis has also been associated with hypoxia and increased hematocrit, constituting a potentially hypercoagulable micro-environment. Furthermore, in animal models, oxygen tension drops very rapidly once blood flow is halted. Abnormalities in these valves as a contributor to thrombotic risk have not been studied extensively at the molecular level. In a recent preliminary study, several of the important vessel based antithrombotic proteins, including thrombomodulin and endothelial protein C receptor (EPCR), were shown to be regionally expressed on the valves. Furthermore, the expression of these proteins showed considerable inter-individual variation. Since expression of these anticoagulant proteins is sensitive to the environment, either hypoxia or inflammation could lead to down regulation, possibly contributing to the initiation of thrombosis. In addition, hypoxia can lead to up-regulation of procoagulant activity including tissue factor on endothelium. Further studies are needed to explore the possibility that changes in the ratio of procoagulant to anticoagulant properties of the valves make a contribution to venous thrombotic risk.

A. The role of blood cells versus vascular contribution to venous thrombosis

In addition to modulating the pro and anticoagulant properties of the endothelium, hypoxia also up regulates the expression of P-selectin on endothelium leading to the recruitment of leukocytes or leukocyte microparticles containing tissue factor which can serve as the nidus for initiation of the thrombotic response. Microparticles bearing tissue factor appear to play a role in thrombus formation. This contrasts to the conventional notion that initiation of coagulation involves exposure of tissue factor on cells surrounding the vessel other than endothelium. This conventional model is attractive because as soon as the vessel is compromised blood comes in contact with extravascular tissue factor sealing the lesion.

The region just downstream of the valve is prone to hypoxia leading to endothelial cell activation. This upregulates adhesion molecules like P-selectin, which in turn can bind to leukocytes or leukocyte microparticles. Since the microparticles contain tissue factor, the interaction with the activated endothelium results in concentrating tissue factor to trigger coagulation that is rapid enough to result in thrombus formation.

There is general agreement that venous thrombosis involves tissue factor as the initiator of the coagulation response. The source of the tissue factor remains somewhat controversial in part because of the model systems used to induce the thrombus in animal models. Most of these involve some type of overt vessel damage. There are clear examples of model systems in which blood borne tissue factor, probably associated with blood cells or microparticles derived from the blood cells, probably leukocytes, is involved in the genesis of the thrombus. One of the first examples where this was shown involved passing human native blood over glass plates covered in collagen. Fibrin clots developed over the slides and this thrombus formation was blocked by antibodies to tissue factor.

Under arterial and venous flow conditions, thrombus also appears to involve P-selectin, an adhesion molecule that can contribute to cell-cell interactions with cells expressing PSGL-1, a major ligand for P-selectin. Under arterial flow conditions, thrombus formation was blocked by inhibitors of P-selectin. Tissue factor and P-selectin appear to both be necessary for thrombus formation and they appear to both be resident on microparticles derived from monocytes, as indicated by the presence of monocyte proteins on the microparticles. In a baboon venous stasis model of thrombosis, P-selectin inhibition was found to prevent thrombus development and facilitate clot resolution. In most of these models, it is difficult to determine whether the tissue factor-P-selectin involvement in thrombus formation is due to cellular interactions or microparticles. It is possible that the interference with thrombosis caused by selectin inhibition is due to inhibiting platelet function or the interaction of platelets with leukocytes and/or leukocyte derived particles in the thrombus. A venous clot is composed of two regions. The red cell rich fibrin clot that appears to lie adjacent to the apparently intact endothelium and lines of platelet rich white thrombus, sometimes called the lines of Zahn, further inside the clot that separate regions of red thrombus. It would seem possible that disrupting the white thrombus areas might render the clot more fragile and/or more susceptible to clot lysis.

A different view of tissue factor involvement in venous thrombosis comes from studies of mice where tissue factor is selectively dramatically reduced in blood cells. In these mice, the blood borne tissue factor contributed little to stasis induced venous thrombosis, indicating that the tissue factor is derived from the vessel wall.

Obviously, these two models seem to be at odds with each other raising questions about why this may be the case. Perhaps the major problem is that each of the models involves vessel injury but the nature and extent of the injury varies. As mentioned previously, except in thrombosis associated with surgery, examination of the human thrombus in the vein seldom indicates evidence of vein injury in the region and thus most human deep vein thrombosis differs from animal models where injury of the vein, even if only by ligation, is usually an initiating event. By injuring the vein, procoagulant membrane surfaces are exposed and adhesive molecules are made available so that leukocytes and platelets will be recruited to the injury site.

A. Additional potential mechanisms for stasis induced venous thrombosis

Many of the anticoagulant pathways are triggered by endothelial cell surface components including thrombomodulin, EPCR, tissue factor pathway inhibitor and heparin like proteoglycans. EPCR and thrombin bound to thrombomodulin initiate the protein C pathway responsible for the inactivation of critical cofactors Va and VIIIa, tissue factor pathway inhibitor blocks tissue factor initiated coagulation and heparin like protoglycans stimulate antithrombin's inhibitor activity toward coagulation enzymes like thrombin, reviewed in. Although the concentration of these proteins does vary somewhat among vascular beds, a major difference is determined by the ratio of endothelial cell surface to blood volume. Therefore, as the blood moves from the larger vessels into the microcirculation, the efficacy of the natural anticoagulants increases dramatically, in large part because of the vastly greater endothelial cell area exposed to blood in the capillaries compared to the major arteries or veins. Presumably, by stasis increasing the residence time in the large vessels, the natural mechanisms for controlling coagulation through interaction with the anticoagulants in the microcirculation are impaired and the propensity to develop thrombi increases with residence time of the blood in the large vessels. This model would be consistent with the known importance of these vascular anticoagulants in preventing thrombosis and the observation that stasis is a major contributor to thrombotic risk.

A. Changes in blood coaguability

Increased levels of coagulation factors, particularly factor VIII, von Willebrand factor, factor VII and prothrombin are associated with an increased risk of thrombosis, reviewed in. The increased risk of thrombosis with the elevation in factor VIII may be due to its inherent instability following activation and hence the need for replenishment to obtain a stable thrombus. In the case of prothrombin, in addition to the potential increase in thrombin generation, prothrombin is also an effective inhibitor of activated protein C anticoagulant activity and hence elevation in prothrombin may function as a double edged sword by directly enhancing thrombin production and by decreasing inhibition of the prothrombin activation.

In thrombophilic families, deficiencies of the main coagulation inhibitors occur in 15%, prothrombin 20210 A occurs in 20% and factor V Leiden occurs in 40-60%. Among the most common changes in blood that increase blood coaguability are defects in natural anticoagulants pathways. There are three major natural anticoagulant pathways; the heparin-antithrombin pathway, the protein C anticoagulant pathway and the tissue factor inhibitor pathway. Of these, defects in antithrombin, and each of the components of the protein C anticoagulant pathway, protein C, protein S, thrombomodulin and possibly EPCR, are associated with increased risks of thrombotic disease in humans. Tissue factor pathway inhibitor defects in human disease remain uncertain, in large part because the majority of the protein is associated with the endothelium and as a result, measuring circulating TFPI levels may not be informative. For all three systems, one or more components of the pathway function at the vessel wall and hence may be sensitive to vascular diseases including inflammation and hypoxia.

A. The influence of aging on thrombosis risk

The risk of thrombosis increases dramatically with aging (Figure 3). The basis for this increase in thrombotic risk with aging remains uncertain. From a population perspective, all of the following increase with age: there are increases in procoagulant levels with age without concomitant increases in natural anticoagulants like protein C, there is an increase in body mass with age, activity decreases often with extended periods of immobilization due to illness, the frequency of acute serious infections rises, frailty increases and the number of co-morbidities tends to mount with age. Surprisingly, although exercise decreases the risk of venous thrombosis slightly in younger individuals, exercise increases this thrombotic risk in the elderly. In addition to the dramatically increased risk of venous thrombosis associated with age, there are also increases in markers of intravascular coagulation such as D-dimer and prothrombin fragment 1- 2 indicating that there is a persistent hypercoaguable state. At present, we do not know if this is due primarily to changes in the vessel wall, perhaps the valves, or the blood. The extent of changes in the circulating blood cells as opposed to the plasma components that might contribute to the increased coagulation is also not known. A better understanding of the basis for the age dependent hypercoaguability might aid in more effective therapies. This is especially important since the bleeding risk on oral anticoagulants rises sharpely in the elderly, making patient management more complex.

Arterial thrombotic risk rises with age in part, presumably, because of increased systemic inflammation such as an increase in IL-6 or C reactive protein but these modest constitutive changes in inflammation appear to have little influence on venous thrombotic risk. However, acute infections do increase risk markedly of both venous thrombosis and pulmonary embolism. Whether the increases in risk are attributable to the acute inflammatory response, increased immobilization or both remains to be determined.

A. Venous thrombosis

A single factor abnormality is seldom enough to cause venous thrombosis leading to “the multiple hit hypothesis.” Although based on human population studies, it is clear that coagulation factor or natural anticoagulant factor levels influence the risk of venous thrombosis, it is equally clear that other factors contribute to thrombotic risk. For example, in some families with protein C deficiency, the incidence of thrombosis is low whereas in other families it is high. In one extended family, the high and low frequencies of thrombosis segregates in certain branches of the family with the protein C deficiency suggesting that there is a strong synergy between multiple factors. Other examples are that while obesity and oral contraceptives independently increase the risk of venous thrombosis, the two together increase the risk synergistically. After correcting for age and sex, obesity >30 Kg/m2 increased the risk of thrombosis two-fold. Obese individuals have increased levels of coagulation factor VIII and IX possibly contributing to the increased risk of thrombosis, but the risk associated with obesity remains even after adjustment for clotting factor levels. Oral contraceptives increase the risk of thrombosis approximately fourfold, and this risk increases to approximately seven-fold for patients with factor V Leiden and 35-fold for patients with factor V Leiden who use oral contraceptives. Likewise, Factor V Leiden and hetozygous protein C deficiency have similar cooperative influences on the risk of thrombosis and this risk remains elevated in the elderly. All of this suggests that there is a thrombosis threshold where the propensity to generate thrombin is not adequately regulated by antithrombotic mechanisms.

Pregnancy

Like oral contraceptives, pregnancy carries an increased risk of developing venous thrombosis that is increased still further in patients with thrombophilia. This increased risk is present in all trimesters of pregnancy and in the post partum period. Potential contributing factors might be disturbed blood flow and hormonal changes.

Cancer

Cancer is a major risk factor for venous thrombosis, increasing the risk about 6-10 fold. Patients with cancer contribute approximately 20% of the new cases of venous thrombosis occuring in the community. Tumors shed membrane particles that contain procoagulant activity including tissue factor and membrane lipids that propogate the coagulation response. Adhesion molecules on the shed particles can help to concentrate the particles at sites where the appropriate ligands for the receptors are present, for instance P-selectin in ischemic areas. By concentrating the procoagulant and procoagulant lipid particles, it is possible to develop a localized thrombus rather than DIC, although DIC is found in some cancer patients. In addition, some tumors may compress one or move veins contributing to stasis.

Lupus Anticoagulants

Paradoxically the presence of lupus anticoagulants in patients is associated with an increased risk of thrombosis despite the fact that these lupus anticoagulant antibodies increase coagulation times in vitro. There are two major mechanisms that might contribute to the thrombotic risk. The antibodies bind to the platelets and endothelium possibly eliciting an inflammatory response. These antibodies also lead to complement activation which appears to contribute to fetal loss. These inflammatory contributions may help to explain why some patients with lupus anticoagulants have increased risks of arterial and/or venous thrombosis. On the venous side, one frequently observed candidate is inhibition of the protein C anticoagulant pathway. In addition, antibodies against thrombomodulin are often found in this patient group and in patients with idiopathic thrombosis, potentially leading to impairment of the protein C anticoagulant pathway.

Post operative thrombosis

Post operative thrombosis is a complication of surgery especially knee, hip and cancer surgery. In the case of knee and hip surgery, damage to the veins in combination with stasis are thought to be major contributing factors. In addition, materials released into the blood stream from the surgical sites can augment coagulation. In the case of cancer surgeries, candidates for contributing to thrombosis include the release of tumor procoagulants, host inflammatory responses and responses to chemotherapeutics.

Conclusion

While epidemiology has identified factors which predispose to venous thrombotic risk, we still lack fundamental knowledge of the basis for the initiation of thrombosis, how exactly the valves are involved in the process and what specific factors are altered with advancing age that contribute so markedly to thrombotic risk. Given the increased risk of major bleeding in the elderly on oral anticoagulants, a better understanding of the basis for the increased risk of thrombosis in the elderly could provide information essential to the design of safer antithrombotics.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are manifestations of a single disease entity, namely, venous thromboembolism (VTE). The earliest known reference to peripheral venous disease is found on the Eber papyrus, which dates from 1550 BC and documents the potentially fatal hemorrhage that may ensue from surgery on varicose veins. In 1644, Schenk first observed venous thrombosis when he described an occlusion in the inferior vena cava. In 1846, Virchow recognized the association between venous thrombosis in the legs and PE.

DVT is the presence of coagulated blood, a thrombus, in one of the deep venous conduits that return blood to the heart. The clinical conundrum is that symptoms (pain and swelling) are often nonspecific or absent. However, if left untreated, the thrombus may become fragmented or dislodged and migrate to obstruct the arterial supply to the lung, causing potentially life- threatening PE See the images below.

DVT most commonly involves the deep veins of the leg or arm, often resulting in potentially life-threatening emboli to the lungs or debilitating valvular dysfunction and chronic leg swelling. Over the past 25 years, the pathophysiology of DVT has become much better understood, and considerable progress has been made in its diagnosis and treatment.

DVT is one of the most prevalent medical problems today, with an annual incidence of 80 cases per 100,000. Each year in the United States, more than 200,000 people develop venous thrombosis; of those, 50,000 cases are complicated by PE. Lower-extremity DVT is the most common venous thrombosis, with a prevalence of 1 case per 1000 population. In addition, it is the underlying source of 90% of acute PEs, which cause 25,000 deaths per year in the United States (National Center for Health Statistics [NCHS], 2006).

Conclusive diagnosis has historically required invasive and expensive venography, which is still considered the criterion standard. The diagnosis may also be obtained noninvasively by means of ultrasonographic examination.

Early recognition and appropriate treatment of DVT and its complications can save many lives. (See Treatment and Management.) The goals of pharmacotherapy for DVT are to reduce morbidity, prevent postthrombotic syndrome (PTS), and prevent PE. The primary agents include anticoagulants and thrombolytics.

Other than the immediate threat of PE, the risk of long-term major disability from postthrombotic syndrome is high.

Etiology Numerous factors, often in combination, contribute to DVT. These may be categorized as acquired (eg, medication, illness) or congenital (eg, anatomic variant, enzyme deficiency, mutation). A useful categorization may be an acute provoking condition versus a chronic condition, as this distinction affects the length of anticoagulant therapy.

The frequent causes of DVT are due to augmentation of venous stasis due to immobilization or central venous obstruction. Immobility can be as transient as that occurring during a transcontinental airplane flight or that during an operation under general anesthesia. It can also be extended, as during hospitalization for pelvic, hip, or spinal surgery, or due to stroke or paraplegia. Individuals in these circumstances warrant surveillance, prophylaxis, and treatment if they develop DVT. Reduced blood flow from increased blood viscosity or central venous pressure Increased blood viscosity may decrease venous blood flow. This change may be due to an increase in the cellular component of the blood in polycythemia rubra vera or thrombocytosis or a decrease in the fluid component due to dehydration.

Increased central venous pressure, either mechanical or functional, may reduce the flow in the veins of the leg. Mass effect on the iliac veins or inferior vena cava from neoplasm, pregnancy, stenosis, or congenital anomaly increases outflow resistance.

Anatomic variants contributing to venous stasis Anatomic variants that result in diminution or absence of the inferior vena cava or iliac veins may contribute to venous stasis. In iliocaval thromboses, an underlying anatomic contributor is identified in 60-80% of patients. The best-known anomaly is compression of left common iliac vein at the anatomic crossing of the right common iliac artery. The vein normally passes under the right common iliac artery during its normal course.

In some individuals, this anatomy results in compression of the left iliac vein and can lead to band or web formation, subsequent stasis, and left leg DVT. The reasons are poorly understood. Compression of the iliac vein is also called May-Thurner syndrome or Cockett syndrome.

Inferior vena cava variants are uncommon. Anomalous development is most commonly detected and diagnosed on cross-sectional imaging or venography. The embryologic evolution of the inferior vena cava is from an enlargement or atrophy of paired supracardinal and subcardinal veins. Anomalous embryologic development may result in absence of the normal cava. These variations may increase the risk of symptoms because small-caliber vessels may be most subject to obstruction. In patients younger than 50 years who have deep venous thrombosis, the incidence of a caval anomaly is as high as 5%.

A double or duplicated inferior vena cava results from lack of atrophy in part of the left supracardinal vein, resulting in a duplicate structure to the left of the aorta. The common form is a partial paired inferior vena cava that connects the left common iliac and left renal veins. When caval interruption, such as placement of a filter, is planned, these alternate pathways must be considered. As an alternative, the inferior vena cava may not develop. The most common alternate route for blood flow is through the azygous vein, which enlarges to compensate. If a venous stenosis is present at the communication of iliac veins and azygous vein, back pressure can result in insufficiency, stasis, or thrombosis.

In rare cases, neither the inferior vena cava nor the azygous vein develops, and the iliac veins drain through internal iliac collaterals to the hemorrhoidal veins and superior mesenteric vein to the portal system of the liver. Hepatic venous drainage to the atrium is patent. Because this pathway involves small hemorrhoidal vessels, thrombosis of these veins can cause severe acute swelling of the legs.

Thrombosis of the inferior vena cava is a rare occurrence and is an unusual result of leg deep venous thrombosis unless an inferior vena cava filter is present and stops a large embolus in the cava, resulting in obstruction and extension of thrombosis. Common causes of caval thrombosis include tumors involving the kidney or liver, tumors invading the inferior vena cava, compression of the inferior vena cava by extrinsic mass, and retroperitoneal fibrosis.

Mechanical injury to vein Mechanical injury to the vein wall appears to provide an added stimulus for venous thrombosis. Hip arthroplasty patients with the associated femoral vein manipulation represent a high-risk group that cannot be explained by just immobilization, with 57% of thrombi originating in the affected femoral vein rather than the usual site of stasis in the calf. Endothelial injury can convert the normally antithrombogenic endothelium to become prothrombotic by stimulating the production of tissue factor, von Willebrand factor, and fibronectin.

Injury may be obvious, such as those due to trauma, surgical intervention, or iatrogenic injury, but they may also be obscure, such as those due to remote deep venous thrombosis (perhaps asymptomatic) or minor (forgotten) trauma. Previous DVT is a major risk factor for further DVT. The increased incidence of DVT in the setting of acute urinary tract or respiratory infection may be due to an inflammation-induced alteration in endothelial function.

According to the results of a meta-analysis of 64 studies encompassing 29,503 patients, peripherally inserted central catheters (PICCs) may double the risk for DVT in comparison with central venous catheters (CVCs). This was the largest review of the incidence, patterns, and risk for VTE associated with PICCs yet published; however, the findings were limited by the absence of any published randomized trials.

Compared with CVCs, PICCs were associated with an increased risk of DVT (odds ratio [OR], 2.55; but not of pulmonary embolism (no events). The frequency of PICC-related DVT was highest in patients who were critically ill (13.91%) and patients who had cancer (6.67%).

Common risk factors for deep venous thrombosis The presence of risk factors plays a prominent role in the assessing the pretest probability of DVT. Furthermore, transient risk factors permit successful short-term anticoagulation, whereas idiopathic deep venous thrombosis or chronic or persistent risk factors warrant long-term therapy.

In the MEDENOX study that evaluated 1102 acutely ill, immobilized admitted general medical patients, multiple logistic regression analysis found the following factors to be significantly and independently associated with an increased risk for VTE, most of which were asymptomatic and diagnosed by venography of both lower extremities :

 Presence of an acute infectious disease  Age older than 75 years  Cancer  History of prior VTE The most common risk factors are obesity, previous VTE, malignancy, surgery, and immobility. Each is found in 20-30% of patients. Hospitalized and nursing home patients often have several risk factors and account for one half of all DVT (with an incidence of 1 case per 100 population).

The single most powerful risk marker remains a prior history of DVT, with as many as 25% of acute venous thrombosis occurring in such patients. Pathologically, remnants of previous thrombi are often seen within the specimens of new acute thrombi. However, recurrent thrombosis may actually be the result of primary hypercoagulable states. Abnormalities within the coagulation cascade are the direct result of discrete genetic mutations within the coagulation cascade. Deficiencies of protein C, protein S, or antithrombin III account for approximately 5- 10% of all cases of DVT.

Age has been well studied as an independent risk factor for venous thrombosis development. Although a 30-fold increase in incidence is noted from age 30 to age 80, the effect appears to be multifactorial, with more thrombogenic risk factors occurring in the elderly than in those younger than 40 years. Venous stasis, as seen in immobilized patients and paralyzed limbs, also contributes to the development of venous thrombosis. Autopsy studies parallel the duration of bed rest to the incidence of venous thrombosis, with 15% of patients in those studies dying within 7 days of bedrest to greater than 80% in those dying after 12 weeks. Within stroke patients, DVT is found in 53% of paralyzed limbs, compared with only 7% on the nonaffected side.

Malignancy is noted in as many as 30% of patients with venous thrombosis.The thrombogenic mechanisms involve abnormal coagulation, as evidenced by 90% of cancer patients having some abnormal coagulation factors. Chemotherapy may increase the risk of venous thrombosis by affecting the vascular endothelium, coagulation cascades, and tumor cell lysis. The incidence has been shown to increase in those patients undergoing longer courses of therapy for breast cancer, from 4.9% for 12 weeks of treatment to 8.8% for 36 weeks. Additionally, DVT complicates 29% of surgical procedures done for malignancy.

Postoperative venous thrombosis varies depending on a multitude of patient factors, including the type of surgery undertaken. Without prophylaxis, general surgery operations typically have an incidence of DVT around 20%, whereas orthopedic hip surgery can occur in up to 50% of patients. The nature of orthopedic illnesses and diseases, trauma, and surgical repair or replacement of hip and knee joints predisposes patients to the occurrence of VTE disease. These complications are predictable and are the result of alterations of the natural equilibrium mechanisms in various disease states. Based on radioactive labeled fibrinogen, about half of lower extremity thrombi develop intraoperatively. Perioperative immobilization, coagulation abnormalities, and venous injury all contribute to the development of surgical venous thrombosis.

Genetic factors Genetic mutations within the blood’s coagulation cascade represent those at highest risk for the development of venous thrombosis. Genetic thrombophilia is identified in 30% of patients with idiopathic venous thrombosis. Primary deficiencies of coagulation inhibitors antithrombin, protein C, and protein S are associated with 5-10% of all thrombotic events. Altered procoagulant enzyme proteins include factor V, factor VIII, factor IX, factor XI, and prothrombin. Resistance of procoagulant factors to an intact anticoagulation system has also recently been described with the recognition of factor V Leiden mutation, representing 10-65% of patients with DVT. In the setting of venous stasis, these factors are allowed to accumulate in thrombosis prone sites, where mechanical vessel injury has occurred, stimulating the endothelium to become prothrombotic. Factor V Leiden is a mutation that results in a form of factor Va that resists degradation by activated protein C, leading to a hypercoagulable state. Its importance lies in the 5% prevalence in the American population and its association with a 3-fold to 6-fold increased risk for VTE. Antiphospholipid syndrome is considered a disorder of the immune system, where antiphospholipid antibodies (cardiolipin or lupus anticoagulant antibodies) are associated with a syndrome of hypercoagulability. Although not a normal blood component, the antiphospholipid antibody may be asymptomatic. It is present in 2% of the population, and it may be detected in association with infections or the administration of certain drugs, including antibiotics, cocaine, hydralazine, procainamide, and quinine.

Tests for these genetic defects are often not performed in patients with recurrent venous thrombosis because therapy remains symptomatic. In most patients with these genetic defects, lifetime anticoagulation therapy with warfarin or low molecular weight heparin (LMWH) is recommended after recurrent DVT without an alternative identifiable etiology documented. The risk of recurrent DVT is multiplied 1.4-2 times, with the most common genetic polymorphisms predisposing individuals to DVT. However, the low incidence of factor V Leiden and prothrombin G20210A may not warrant aggressive prophylaxis. Therefore, genetic testing might not be warranted until a second event occurs.

Other conditions that can induce hypercoagulability Other diseases and states can induce hypercoagulability in patients without other underlying risks for DVT. They can predispose patients to DVT, though their ability to cause DVT without intrinsic hypercoagulability is in question. The conditions include malignancy, dehydration, and use of medications (eg, estrogens). Acute hypercoagulable states also occur, as in disseminated intravascular coagulopathy (DIC) resulting from infection or heparin-induced thrombocytopenia.

Summary of risk factors A summary of risk factors is as follows:

 Age  Immobilization longer than 3 days  Pregnancy and the postpartum period  Major surgery in previous 4 weeks  Long plane or car trips (> 4 hours) in previous 4 weeks  Cancer  Previous DVT  Stroke  Acute myocardial infarction (AMI)  Congestive heart failure (CHF)  Sepsis  Nephrotic syndrome  Ulcerative colitis  Multiple trauma  CNS/spinal cord injury  Burns  Lower extremity fractures  Systemic lupus erythematosus (SLE) and the lupus anticoagulant  Behçet syndrome  Homocystinuria  Polycythemia rubra vera  Thrombocytosis  Inherited disorders of coagulation/fibrinolysis  Antithrombin III deficiency  Protein C deficiency  Protein S deficiency  Prothrombin 20210A mutation  Factor V Leiden  Dysfibrinogenemias and disorders of plasminogen activation  Intravenous (IV) drug abuse  Oral contraceptives  Estrogens  Heparin-induced thrombocytopenia (HIT)

Epidemiology DVT and thromboembolism remain a common cause of morbidity and mortality in bedridden or hospitalized patients, as well as generally healthy individuals. The exact incidence of DVT is unknown because most studies are limited by the inherent inaccuracy of clinical diagnosis. Existing data that probably underestimate the true incidence of DVT suggest that about 80 cases per 100,000 population occur annually. Approximately 1 person in 20 develops a DVT in the course of his or her lifetime. About 600,000 hospitalizations per year occur for DVT in the United States.

In elderly persons, the incidence is increased 4-fold. The in-hospital case-fatality rate for VTE is 12%, rising to 21% in elderly persons. In hospitalized patients, the incidence of venous thrombosis is considerably higher and varies from 20-70%. Venous ulceration and venous insufficiency of the lower leg, which are long-term complications of DVT, affect 0.5% of the entire population. Extrapolation of these data reveals that as many as 5 million people have venous stasis and varying degrees of venous insufficiency.

Age distribution for deep venous thrombosis Deep venous thrombosis usually affects individuals older than 40 years. The incidence of VTE increases with age in both sexes. The age-standardized incidence of first-time VTE is 1.92 per 1000 person-years.

Prevalence of deep venous thrombosis by sex The male-to-female ratio is 1.2:1, indicating that males have a higher risk of DVT than females.

Prevalence of deep venous thrombosis by race From a demographic viewpoint, Asian and Hispanic populations have a lower risk of VTE, whereas whites and blacks have a higher risk (2.5-4 times higher).

Physical Examination No single physical finding or combination of symptoms and signs is sufficiently accurate to establish the diagnosis of DVT.

The classic finding of calf pain on dorsiflexion of the foot (Homans sign) is specific but insensitive and present in one half of patients with DVT. Discomfort in the calf muscles on forced dorsiflexion of the foot with the knee straight has been a time-honored sign of DVT. However, Homans sign is neither sensitive nor specific: it is present in less than one third of patients with confirmed DVT, and is found in more than 50% of patients without DVT.

Superficial thrombophlebitis is characterized by the finding of a palpable, indurated, cordlike, tender, subcutaneous venous segment. Forty percent of patients with superficial thrombophlebitis without coexisting varicose veins and with no other obvious etiology (eg, intravenous catheters, intravenous drug abuse, soft tissue injury) have an associated DVT. Patients with superficial thrombophlebitis extending to the saphenofemoral junction are also at higher risk for associated DVT.

If a patient is thought to have PE or has documented PE, the absence of tenderness, erythema, edema, or a palpable cord upon examination of the lower extremities does not rule out thrombophlebitis, nor does it imply a source other than a leg vein. More than two thirds of patients with proven PE lack any clinically evident phlebitis. Nearly one third of patients with proven PE have no identifiable source of DVT, despite a thorough investigation. Autopsy studies suggest that even when the source is clinically inapparent, it lies undetected within the deep venous system of the lower extremity and pelvis in 90% of cases.

Patients with venous thrombosis may have variable discoloration of the lower extremity. The most common abnormal hue is reddish purple from venous engorgement and obstruction. In rare cases, the leg is cyanotic from massive ileofemoral venous obstruction. This ischemic form of venous occlusion was originally described as phlegmasia cerulea dolens (“painful blue inflammation”). The leg is usually markedly edematous, painful, and cyanotic. Petechiae are often present.

In relatively rare instances, acute extensive (lower leg–to-iliac) occlusion of venous outflow may create a blanched appearance of the leg because of edema. The clinical triad of pain, edema, and blanched appearance is termed phlegmasia alba dolens (“painful white inflammation”), a term originally used to describe massive ileofemoral venous thrombosis and associated arterial spasm. This is also known as milk-leg syndrome when it is associated with compression of the iliac vein by the gravid uterus. The affected extremity is often pale with poor or even absent distal pulses. The physical findings may suggest acute arterial occlusion, but the presence of swelling, petechiae, and distended superficial veins point to this condition. As many as half the patients with phlegmasia alba dolens have capillary involvement, which poses a risk of irreversible venous gangrene with massive fluid sequestration. In severely affectedpatients, immediate therapyisnecessarytoprevent limb loss. Pulmonary Embolism As many as 40% of patients have silent PE when symptomatic DVT is diagnosed. Approximately 4% of individuals treated for DVT develop symptomatic PE. Almost 1% of postoperative hospitalized patients develop PE. The 10-12% mortality rate for PE in hospitalized patients underscores the need for prevention of this complication. Treatment options include anticoagulation therapy and placement of an inferior vena cava filter. If evidence of right heart failure is present or if adequate oxygenation cannot be maintained, the thrombus may be removed with pharmacomechanical thrombolytic intervention.

PE is most often diagnosed by means of ventilation/perfusion lung scanning, which is reported as having a low, moderate, or high probability of depicting PE. When the results of these studies are equivocal, the use of spiral CT scans may be able to demonstrate intravascular thrombosis. In many institutions, the criterion standard for diagnosing PE is pulmonary angiography. Without treatment, one half of patients have a recurrent, symptomatic VTE event within 3 months. After anticoagulation for an unprovoked VTE event is discontinued, the incidence is 5- 15% per year. Presentations are similar, with pain and edema. However, the diagnosis may be difficult (ie, differentiating acute from chronic thrombus). Recurrence increases the risk of postthrombotic syndrome PTS is a chronic complication of DVT that manifests months to many years after the initial event. Symptoms range from mild erythema and localized induration to massive extremity swelling and ulceration, usually exacerbated by standing and relieved by elevation of the extremity. Evaluations of the incidence or of improvements with therapy have been problematic because reporting is not standardized. Furthermore, correlation between objectively measured hemodynamic changes and the severity of PTS is poor.

After symptomatic DVT is treated with anticoagulation, the incidence of PTS at 2 years is 25- 50% despite long-term anticoagulation for iliofemoral DVT, and after 7-10 years, the incidence is 70-90%. The only current treatment is use of a compression hose and elevation. In many patients, this is only partly effective in relieving swelling, pain, and venous ulcers. In the United States, the annual direct cost of post–DVT, PTS-related venous ulcers is estimated to be $45 million per year, and 300,000 work days are lost.

Approach Considerations A clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians provides 4 recommendations for the workup of patients with probable DVT. First, validated clinical prediction rules should be used to estimate the pretest probability of VTE and interpret test results. The Wells prediction rules for DVT and for pulmonary embolism meet this standard, although the rule performs better in younger patients without comorbidities or a history of VTE than it does in other patients.

Second, in appropriately selected patients with low pretest probability of DVT or pulmonary embolism, it is reasonable to obtain a high-sensitivity D-dimer. A negative result indicates a low likelihood of VTE. Third, in patients with intermediate to high pretest probability of lower- extremity DVT, ultrasonography is recommended. Fourth, patients with intermediate or high pretest probability of pulmonary embolism require diagnostic imaging studies. Options include a ventilation-perfusion (V/Q) scan, multidetector helical computed axial tomography (CT), and pulmonary angiography; however, CT alone may not be sufficiently sensitive to exclude pulmonary embolism in patients who have a high pretest probability of pulmonary embolism.

Venous thromboembolism (VTE) remains an underdiagnosed disease, and most cases of pulmonary embolism (PE) are diagnosed at autopsy. Diagnosis depends on a high level of clinical suspicion and the presence of risk factors that prompt diagnostic study. Because the presentation is nonspecific and because the consequence of missing the diagnosis is serious, it must be excluded whenever it is a feasible differential diagnosis. Because the prevalence of the disease is 15-30% in the population at clinical risk, a widely applicable (inexpensive and simple) screening test is required.

Conclusive diagnosis historically required invasive and expensive venography, which is still considered the criterion standard. Since 1990, the diagnosis has been obtained noninvasively by means of (still expensive) sonographic examination. The recent validation of the simpler and cheaper D-dimer test as an initial screening test permits a rapid, widely applicable screening that may reduce the rate of missed diagnoses. Algorithms are based on pretest probabilities and D- dimer results. As many of 40% of patients with a low clinical suspicion and a negative D-dimer result require no further evaluation.

Laboratory analysis has also been used in aiding the diagnosis of venous thrombosis. Protein S, protein C, antithrombin III (ATIII), factor V Leiden, prothrombin 20210A mutation, antiphospholipid antibodies, and homocysteine levels can be measured. Deficiencies of these factors or the presence of these abnormalities all produce a hypercoagulable state. These are rare causes of deep venous thrombosis (DVT). Laboratory investigations for these abnormalities are primarily indicated when DVT is diagnosed in patients younger than 50 years, when there is a confirmed family history of a hypercoagulable state or a familial deficiency, when venous thrombosis is detected in unusual sites, and in the clinical setting of warfarin-induced skin necrosis.

Coagulation Profile Additional blood work should include coagulation studies to evaluate for a hypercoagulable state, if clinically indicated. A prolonged prothrombin time or activated partial thromboplastin time does not imply a lower risk of new thrombosis. Progression of DVT and PE can occur despite full therapeutic anticoagulation in 13% of patients.

Imaging in Deep Venous Thrombosis Imaging studies used in DVT include ultrasonography, venography, impedance plethysmography, MRI, and nuclear imaging. Ultrasonography is the current first-line imaging examination for DVT because of its relative ease of use, absence of irradiation or contrast material, and high sensitivity and specificity in institutions with experienced sonographers.

The criterion standard to diagnostic imaging for DVT remains venography with pedal vein cannulation, intravenous contrast injection, and serial limb radiographs. However, the invasive nature and significant consumption of resources are only 2 of its many limitations. In some countries, impedance plethysmography (IPG) has been the initial noninvasive diagnostic test of choice and has been shown to be sensitive and specific for proximal vein thrombosis. However, IPG also has several other limitations; among them are insensitivity for calf vein thrombosis, nonoccluding proximal vein thrombus, and iliofemoral vein thrombosis above the inguinal ligament.

MRI has increasingly been investigated for evaluation of suspected DVT. Limited studies suggest the accuracy approaches that of contrast venography. MRI is the diagnostic test of choice for suspected iliac vein or inferior vena caval thrombosis when CT venography is contraindicated or technically inadequate. Radiolabeled peptides that bind to various components of a thrombus have been investigated. The cost of the tests and the inability to visualize the anatomy of the area of involvement (which many clinicians prefer) has lead to the underuse of scintigraphy.

Additionally, note that imaging modalities, techniques, and findings may be specific to the upper extremities and lower extremities.

Treatment General Principles of Anticoagulation Anticoagulant therapy remains the mainstay of medical therapy for DVT because it is noninvasive, it treats most patients (approximately 90%) with no immediate demonstrable physical sequelae of DVT, it has a low risk of complications, and its outcome data demonstrate an improvement in morbidity and mortality. Long-term anticoagulation is necessary to prevent the high frequency of recurrent venous thrombosis or thromboembolic events. Anticoagulation does have problems. Although it inhibits propagation, it does not remove the thrombus, and a variable risk of clinically significant bleeding is observed.

Heparin Use in Deep Venous Thrombosis Heparin products used in the treatment of deep venous thrombosis (DVT) include unfractionated heparin and low molecular weight heparin (LMWH) The efficacy and safety of LMWH for the initial treatment of deep venous thrombosis have been well established in several trials. Traditionally, heparin has been used only for admitted patients with DVT. Regular unfractionated heparin was the standard of care until the introduction of LMWH products. Heparin prevents extension of the thrombus and has been shown to significantly reduce (but not eliminate) the incidence of fatal and nonfatal pulmonary embolism and recurrent thrombosis.

Heparin is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biological activity. The larger fragments exert their anticoagulant effect by interacting with antithrombin III (ATIII) to inhibit thrombin. ATIII, the body’s primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X in the coagulation process. The low-molecular-weight fragments exert their anticoagulant effect by inhibiting the activity of activated factor X. The hemorrhagic complications attributed to heparin are thought to arise from the larger higher-molecular-weight fragments. LMWH is prepared by selectively treating unfractionated heparin to isolate the low molecular weight (< 9000 Da) fragments. Duration of Heparin Therapy The practice of a 7- to 10-day course of heparin therapy has been changed because of the findings of two randomized studies performed in patients with DVT. The studies reported that a 4- to 5-day course of heparin was as effective as a 9- to 10-day course of heparin. The results of these two studies have important practical implications because the shorter course of heparin facilitates early discharge of patients from the hospital. Although the findings of these studies can likely be generalized to most patients, they may not be applicable to patients with large iliofemoral vein thrombosis or major PE, because these two classes of patients were excluded from one study and formed only a small proportion of patients in the second. It is our practice to treat patients with large iliofemoral vein thrombi and those with major PE with a 7- to 10-day course of heparin and to delay starting warfarin therapy until the aPTT has been in the therapeutic range for 3 days. The delay in starting warfarin is used to ensure that patients receive an adequate dose of heparin for at least 5 days.

Low-Molecular-Weight Heparins Administration of LMWHs in a fixed dose by subcutaneous injection has been compared with administration of dose-adjusted heparin by continuous infusion for treatment of venous thrombosis. The results, which have been summarized in a meta-analysis, indicate that LMWHs are at least as effective and safe as standard heparin. These findings raise the possibility that selected patients with venous thrombosis might be suitable candidates for treatment at home, an advance that would reduce cost and improve patient convenience. Like heparin, LMWHs do not cross the placental barrier, and descriptive studies suggest they might be safe and effective in pregnancy. In a randomized trial LMWHs were associated with a much lower incidence of heparin-induced thrombocytopenia than heparin and a lower incidence of osteoporosis.

Oral Anticoagulants The need for oral anticoagulants after an initial course of heparin is based on the results of two randomized studies that demonstrated that the incidence of out-of-hospital recurrences could be markedly reduced if heparin therapy was followed by a 3-month course of warfarin. In one study in which the dose of warfarin was adjusted to obtain an INR of 3.0 to 4.5, the incidence of bleeding was very high. Another study was then conducted in which patients with proximal vein thrombosis were randomly assigned to treatment with either high- (INR, 3.0 to 4.5) or moderate- intensity (INR, 2.0 to 3.0) warfarin after an initial course of heparin therapy. The incidence of recurrence was equally low in both groups, but bleeding was approximately four times higher in the high-intensity group. Based on the results of this study, and subsequent experience with other prospective clinical studies, the recommended therapeutic range is an INR of 2.0 to 3.0. An INR of 3.0 to 4.0 has been recommended for patients with antiphospholipid antibodies, although there is some disagreement on this issue. Antithrombotic Effect of Warfarin Warfarin therapy is usually monitored by prothrombin time (PT), a test that is responsive to reduction of 3 of the 4 vitamin K–dependent procoagulant clotting factors (factors II, VII, and X). The conventional view is that the antithrombotic effect of warfarin is reflected by its anticoagulant effect as measured by PT. However, this view may not be correct during the induction phase of warfarin therapy. During the first few days of warfarin therapy, PT primarily reflects the reduction of factor VII activity, which has a half-life of only ≈6 hours, which is similar to the half-life of the natural anticoagulant protein C. Subsequently PT is prolonged by depression of factors X and II (prothrombin). Therefore, for the first 24 hours of warfarin therapy there is potential for a transient hypercoagulable state, resulting from a reduction of levels of protein C before the effects of warfarin on the activities of factors X and II are fully expressed. There is evidence that reductions of factor II and, possibly, factor X are more important than reduction of factors VII and IX for the antithrombotic effect of warfarin. The evidence supporting this view comes from the following observations. First, the experiments of Wessler and Gitel,175 performed more than 40 years ago with a stasis model of thrombosis in rabbits, showed that the antithrombotic effects of warfarin require 6 days of treatment, whereas the anticoagulant effect of warfarin as reflected by prolongation of PT is seen within 2 days. These findings are consistent with an explanation that the antithrombotic effect of warfarin requires a reduction in activity of factor II, which has a half-life of ≈60 hours. Second, in more recent experiments in a rabbit model of tissue factor–induced intravascular coagulation, Zivelin et al176demonstrated that the protective effect of warfarin primarily reflects its ability to lower factor II levels. Thus, selective infusion of factor II, and to a lesser extent factor X, abolished the protective effects of warfarin in this model. In contrast, infusion of factor VII or IX had no effect.

The concept that the antithrombotic effect of warfarin reflects its ability to lower factor II levels provides a rationale for overlapping heparin with warfarin in treatment of patients with thrombotic disease until the factor II level is lowered into the therapeutic range. Given that factor II has a half-life of ≈60 hours, an overlap of at least 4 days is necessary.

Recommendations for Duration of Warfarin Therapy

Patients with a first episode of VTE should be treated for 6 weeks to 3 months if they have a reversible risk factor and for 3 to 6 months if they have idiopathic venous thrombosis. Warfarin therapy should be continued for longer periods, possibly for life, in patients with documented idiopathic thrombosis who have 1 of the 4 inherited molecular abnormalities (deficiencies of AT- III, protein C, protein S, or activated protein C resistance) and in those who have a lupus anticoagulant or anticardiolipin antibody, because these laboratory abnormalities predispose them to recurrent venous thrombosis. Treatment of patients with these blood abnormalities who develop venous thrombosis after a well-recognized provocation (eg, surgery) is uncertain. Indefinite anticoagulation might not be warranted, although some authorities believe so. The AHA also recommends that patients who have more than two documented episodes of recurrent venous thrombosis and patients with at least one episode of thrombosis and active cancer should be treated with anticoagulants indefinitely. Finally, patients with ongoing risk factors (eg, immobilization in a plaster cast) should be treated until the period of risk is over.

Most patients requiring long-term anticoagulant therapy respond well to warfarin targeted to an INR of 2.0 to 3.0. However, some patients with cancer have a resistance to warfarin and require long-term treatment with heparin, administered in full doses by subcutaneous injection. The optimal intensity of anticoagulation therapy is uncertain for patients with a lupus anticoagulant or cardiolipin antibody who require long-term anticoagulation. There are reports, based on retrospective analyses of observational studies, that patients with the antiphospholipid antibody syndrome and thrombosis are inadequately protected from recurrent episodes of VTE if treated at a targeted INR of 2.0 to 3.0. In contrast, a recent smaller prospective study in lupus anticoagulant–positive patients with venous thrombosis but without other manifestations of the antiphospholipid antibody syndrome reported that these patients with fewer complications respond well to warfarin at an INR intensity of 2.0 to 3.0. It is uncertain whether the discrepant findings reported in these studies result from differences in patient populations or differences in the responsiveness of PT reagents to the lupus anticoagulant in patients who receive anticoagulation with warfarin. Thus, it is possible that with some PT reagents the INR result is artifactually prolonged by the lupus anticoagulant and therefore does not reflect the true anticoagulant effects of warfarin.

General Principles of Endovascular Intervention Percutaneous transcatheter treatment of patients with deep venous thrombosis (DVT) consists of thrombus removal with catheter-directed thrombolysis, mechanical thrombectomy, angioplasty, and/or stenting of venous obstructions. Consensus has been reached regarding indications for the procedure, although it is based on midlevel evidence from nonrandomized controlled trials. The goals of endovascular therapy include reducing the severity and duration of lower-extremity symptoms, preventing pulmonary embolism, diminishing the risk of recurrent venous thrombosis, and preventing postthrombotic syndrome. A randomized controlled trial comparing catheter-directed thrombolysis to conventional anticoagulation demonstrated a lower incidence of postthrombotic syndrome and improved iliofemoral patency in patients with a high proximal DVT and low risk of bleeding.

Indications for intervention include the relatively rare phlegmasia or symptomatic inferior vena cava thrombosis that responds poorly to anticoagulation alone, or symptomatic iliofemoral or femoropopliteal DVT in patients with a low risk of bleeding. Contraindications are the same as those for thrombolysis in general. Absolute contraindications include active internal bleeding or disseminated intravascular coagulation, a cerebrovascular event, trauma, or neurosurgery within 3 months. Unfortunately, most patients with DVT have absolute contraindications to thrombolytic therapy. Currently, the American College of Chest Physicians (ACCP) consensus guidelines recommend thrombolytic therapy only for patients with massive ileofemoral vein thrombosis associated with limb ischemia or vascular compromise.

Percutaneous mechanical thrombectomy devices are a popular adjunct to catheter-directed thrombolysis. Although these devices may not completely remove thrombus, they are effective for debulking and for minimizing the dose and time required for infusing a thrombolytic. Percutaneous mechanical thrombectomy has developed as an attempt to shorten treatment time and avoid costly ICU stays during thrombolytic infusion. The most basic mechanical method for thrombectomy is thromboaspiration, or the aspiration of thrombus through a sheath. Mechanical disruption of venous thrombosis has the potential disadvantage of damaging venous endothelium and valves, in addition to thrombus fragmentation and possible pulmonary embolism.

Pulmonary embolism

Pulmonary embolism (PE) is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream (embolism). PE most commonly results from deep vein thrombosis (a blood clot in the deep veins of the legs or pelvis) that breaks off and migrates to the lung, a process termedvenous thromboembolism (VTE). A small proportion of cases are caused by the embolization of air, fat, or talc in drugs of intravenous drug abusers or amniotic fluid. The obstruction of the blood flow through the lungs and the resultant pressure on the right ventricle of the heart lead to the symptoms and signs of PE. The risk of PE is increased in various situations, such as cancer or prolonged bed rest. Symptoms of pulmonary embolism include difficulty breathing, chest pain on inspiration, and palpitations. Clinical signs include low blood oxygen saturation and cyanosis, rapid breathing, and a rapid heart rate. Severe cases of PE can lead to collapse, abnormally low blood pressure, and sudden death. Diagnosis is based on these clinical findings in combination with laboratory tests (such as the D-dimer test) and imaging studies, usually CT pulmonary angiography. Treatment is typically with anticoagulant medication, including heparin and warfarin. Severe cases may require thrombolysis using medication such as tissue plasminogen activator (tPA), or may require surgical intervention via pulmonary thrombectomy.

Signs and symptoms Symptoms of PE are typically sudden in onset and may include one or many of the following: dyspnea (shortness of breath), tachypnea (rapid breathing), chest pain of a "pleuritic" nature (worsened by breathing), cough andhemoptysis (coughing up blood). More severe cases can include signs such as cyanosis (blue discoloration, usually of the lips and fingers), collapse, and circulatory instability because of decreased blood flow through the lungs and into the left side of the heart. About 15% of all cases of sudden death are attributable to PE. On physical examination, the lungs are usually normal. Occasionally, a pleural friction rub may be audible over the affected area of the lung (mostly in PE with infarct). A pleural effusion is sometimes present that is exudative, detectable by decreased percussion note, audible breath sounds and vocal resonance. Strain on the right ventricle may be detected as a left parasternal heave, a loud pulmonary component of the second heart sound, and raised jugular venous pressure.[1] A low-grade fever may be present, particularly if there is associated pulmonary hemorrhage or infarction.[2] As smaller PEs tend to lodge in more peripheral areas without collateral circulation they are more likely to cause lung infarction and small effusions (both of which are painful), but not hypoxia, dyspnea or hemodynamic instability such as tachycardia. Larger PEs, which tend to lodge more centrally, typically cause dyspnea, hypoxia, hypotension, tachycardia and syncope, but are often painless because there is no lung infarction due to collateral circulation. The classic presentation for PE with pleuritic pain, dyspnea and tachycardia is most likely to be caused by a large embolism that fragments and thus causes both large and small PEs. Thus, small PEs are often missed because they cause pleuritic pain alone without any other findings and large PEs are often missed because they are painless and mimic other conditions often causing EKG changes and small rises in troponin and BNP levels. PEs are sometimes described as massive, submassive and nonmassive depending on the clinical signs and symptoms. Although the exact definitions of these are unclear, a generally accepted definition of massive PE is one in which there is hemodynamic instability such as sustained hypotension, bradycardia or pulselessness.

Risk factors

A deep vein thrombosis as seen in the right leg is a risk factor for PE

The most common sources of embolism are proximal leg deep vein thromboses (DVTs) or pelvic vein thromboses. Any risk factor for DVT also increases the risk that the venous clot will dislodge and migrate to the lung circulation, which may happen in as many as 15% of all DVTs. The conditions are generally regarded as a continuum termed venous thromboembolism (VTE). The development of thrombosis is classically due to a group of causes named Virchow's triad (alterations in blood flow, factors in the vessel wall and factors affecting the properties of the blood). Often, more than one risk factor is present.

 Alterations in blood flow: immobilization (after surgery, injury, pregnancy (also procoagulant), obesity (also procoagulant), cancer (also procoagulant)  Factors in the vessel wall: surgery, catheterizations causing direct injury ("endothelial injury")  Factors affecting the properties of the blood (procoagulant state):  Estrogen-containing hormonal contraception  Genetic thrombophilia (factor V Leiden, prothrombin mutation G20210A, protein C deficiency, protein S deficiency, antithrombin deficiency, hyperhomocysteinemia andplasminogen/fibrinolysis disorders)  Acquired thrombophilia (antiphospholipid syndrome, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria)  Cancer (due to secretion of pro-coagulants) Underlying causes After a first PE, the search for secondary causes is usually brief. Only when a second PE occurs, and especially when this happens while still under anticoagulant therapy, a further search for underlying conditions is undertaken. This will include testing ("thrombophilia screen") for Factor V Leiden mutation, antiphospholipid antibodies, protein C and S and antithrombin levels, and later prothrombin mutation, MTHFR mutation, Factor VIII concentration and rarer inherited coagulation abnormalities.

Diagnosis

A Hampton hump in a person with a right lower lobe pulmonary embolism

To diagnose pulmonary embolism, medical societies recommend a review of clinical criteria to determine the need for testing, followed by testing to determine a likelihood of being able to confirm a diagnosis by imaging, followed by imaging if other tests have shown that there is a likelihood of a PE diagnosis. The diagnosis of PE is based primarily on validated clinical criteria combined with selective testing because the typical clinical presentation (shortness of breath, chest pain) cannot be definitively differentiated from other causes of chest pain and shortness of breath. The decision to do medical imaging is usually based on clinical grounds, i.e. the medical history, symptoms and findings on physical examination, followed by an assessment of clinical probability. The most commonly used method to predict clinical probability, the Wells score, is a clinical prediction rule, whose use is complicated by multiple versions being available. In 1995, Wells et al. initially developed a prediction rule (based on a literature search) to predict the likelihood of PE, based on clinical criteria. The prediction rule was revised in 1998 . This prediction rule was further revised when simplified during a validation by Wells et al. in 2000. In the 2000 publication, Wells proposed two different scoring systems using cutoffs of 2 or 4 with the same prediction rule. In 2001, Wells published results using the more conservative cutoff of 2 to create three categories. An additional version, the "modified extended version", using the more recent cutoff of 2 but including findings from Wells's initial studies were proposed. Most recently, a further study reverted to Wells's earlier use of a cutoff of 4 points to create only two categories. There are additional prediction rules for PE, such as the Geneva rule. The Wells score:

 clinically suspected DVT — 3.0 points  alternative diagnosis is less likely than PE — 3.0 points  tachycardia (heart rate > 100) — 1.5 points  immobilization (≥ 3d)/surgery in previous four weeks — 1.5 points  history of DVT or PE — 1.5 points  hemoptysis — 1.0 points  malignancy (with treatment within 6 months) or palliative — 1.0 points Traditional interpretation

 Score >6.0 — High (probability 59% based on pooled data)  Score 2.0 to 6.0 — Moderate (probability 29% based on pooled data)  Score <2.0 — Low (probability 15% based on pooled data) Alternative interpretation

 Score > 4 — PE likely. Consider diagnostic imaging.  Score 4 or less — PE unlikely. Consider D-dimer to rule out PE. Blood tests In people with a low or moderate suspicion of PE, a normal D-dimer level (shown in a blood test) is enough to exclude the possibility of thrombotic PE, with a three-month risk of thromboembolic events being 0.14%. D- dimer is highly sensitive but not very specific (specificity around 50%). In other words, a positive D-dimer is not synonymous with PE, but a negative D-dimer is, with a good degree of certainty, an indication of absence of a PE. The typical cut off is 500 ug/L. However, in those over the age of 50, changing the cut-off value to the persons age multiplied by 10 ug/L decreases the number of falsely positive tests without missing any additional cases of PE. When a PE is being suspected, a number of blood tests are done in order to exclude important secondary causes of PE. This includes a full blood count, clotting status (PT, aPTT, TT), and some screening tests (erythrocyte sedimentation rate, renal function, liver enzymes, electrolytes). If one of these is abnormal, further investigations might be warranted. Imaging

Selective pulmonary angiogramrevealing significant thrombus (labelled A) causing a central obstruction in the left main pulmonary artery. ECG tracing shown at bottom.

CT pulmonary angiography (CTPA) showing a "saddle embolus" at the bifurcation of the pulmonary artery and substantial thrombus burden in the lobar branches of both main pulmonary arteries.

Ventilation-perfusion scintigraphy in a woman taking hormonal contraceptives and valdecoxib. (A) After inhalation of 20.1 mCi ofXenon-133 gas, scintigraphic images were obtained in the posteriorprojection, showing uniform ventilation to lungs. (B) After intravenous injection of 4.1 mCi of Technetium-99m-labeled macroaggregated albumin, scintigraphic images were obtained, shown here in the posterior projection. This and other views showed decreased activity in multiple regions.

In typical people who are not known to be at high risk of PE, imaging is helpful to confirm or exclude a diagnosis of PE after simpler first-line tests are used. Medical societies recommend tests such as the D- dimer to first provide supporting evidence for the need for imaging, and imaging would be done if other tests confirmed a moderate or high probability of finding evidence to support a diagnosis of PE. CT pulmonary angiography is the recommended first line diagnostic imaging test in most people. Historically, the gold standard for diagnosis was pulmonary angiography, but this has fallen into disuse with the increased availability of non-invasive techniques. Non-invasive imaging CT pulmonary angiography (CTPA) is a pulmonary angiogram obtained using computed tomography (CT) with radiocontrast rather than right heart catheterization. Its advantages are clinical equivalence, its non- invasive nature, its greater availability to people, and the possibility of identifying other lung disorders from the differential diagnosis in case there is no pulmonary embolism. Assessing the accuracy of CT pulmonary angiography is hindered by the rapid changes in the number of rows of detectors available in multidetector CT (MDCT) machines. According to a cohort study, single-slice spiral CT may help diagnose detection among people with suspected pulmonary embolism. In this study, the sensitivity was 69% and specificity was 84%. In this study which had a prevalence of detection was 32%, the positive predictive value of 67.0% and negative predictive value of 85.2% (click here to adjust these results for people at higher or lower risk of detection). However, this study's results may be biased due to possible incorporation bias, since the CT scan was the final diagnostic tool in people with pulmonary embolism. The authors noted that a negative single slice CT scan is insufficient to rule out pulmonary embolism on its own. A separate study with a mixture of 4 slice and 16 slice scanners reported a sensitivity of 83% and a specificity of 96%. This study noted that additional testing is necessary when the clinical probability is inconsistent with the imaging results. CTPA is non-inferior to VQ scanning, and identifies more emboli (without necessarily improving the outcome) compared to VQ scanning. A ventilation/perfusion scan (or V/Q scan or lung scintigraphy) shows that some areas of the lung are being ventilated but not perfused with blood (due to obstruction by a clot). This type of examination is as accurate as multislice CT, but is less used, due to the greater availability of CT technology. It is particularly useful in people who have an allergy to iodinated contrast, impaired renal function, or are pregnant (due to its lower radiation exposure as compared to CT). The test can be performed with planar two-dimensional imaging, or single photon emission tomography (SPECT) which enables three-dimensional imaging. Hybrid devices combining SPECT and CT (SPECT/CT) further enable anatomic characterization of any abnormality. Low probability diagnostic tests/non-diagnostic tests Tests that are frequently done that are not sensitive for PE, but can be diagnostic.

 Chest X-rays are often done on people with shortness of breath to help rule-out other causes, such as congestive heart failure and rib fracture. Chest X-rays in PE are rarely normal, but usually lack signs that suggest the diagnosis of PE (e.g. Westermark sign, Hampton's hump).  Ultrasonography of the legs, also known as leg doppler, in search of deep venous thrombosis (DVT). The presence of DVT, as shown on ultrasonography of the legs, is in itself enough to warrant anticoagulation, without requiring the V/Q or spiral CT scans (because of the strong association between DVT and PE). This may be valid approach in pregnancy, in which the other modalities would increase the risk of birth defects in the unborn child. However, a negative scan does not rule out PE, and low-radiation dose scanning may be required if the mother is deemed at high risk of having pulmonary embolism. Electrocardiogram

Electrocardiogram of a person with pulmonary embolism, showing sinus tachycardia of approximately 150 beats per minute and right bundle branch block.

The primary use of the ECG is to rule out other causes of chest pain. An electrocardiogram (ECG) is routinely done on people with chest pain to quickly diagnose myocardial infarctions(heart attacks), an important differential diagnosis in an individual with chest pain. While certain ECG changes may occur with PE, none are specific enough to confirm or sensitive enough to rule out the diagnosis.] An ECG may show signs of right heart strain or acute cor pulmonale in cases of large PEs — the classic signs are a large S wave in lead I, a large Q wave in lead III, and an inverted T wave in lead III (S1Q3T3), which occurs in 12-50% of people with the diagnosis, yet also occurs in 12% without the diagnosis. This is occasionally present (occurring in up to 20% of people), but may also occur in other acute lung conditions, and, therefore, has limited diagnostic value. The most commonly-seen signs in the ECG are sinus tachycardia, right axis deviation, and right bundle branch block. Sinus tachycardia, however, is still only found in 8–69% of people with PE. Echocardiography In massive and submassive PE, dysfunction of the right side of the heart may be seen on echocardiography, an indication that the pulmonary artery is severely obstructed and the right ventricle, a low pressure pump, is unable to match the pressure. Some studies (see below) suggest that this finding may be an indication for thrombolysis. Not every person with a (suspected) pulmonary embolism requires an echocardiogram, but elevations in cardiac troponins or brain natriuretic peptide may indicate heart strain and warrant an echocardiogram,and be important in prognosis. The specific appearance of the right ventricle on echocardiography is referred to as the McConnell's sign. This is the finding of akinesia of the mid-free wall but normal motion of the apex. This phenomenon has a 77% sensitivity and a 94% specificity for the diagnosis of acute pulmonary embolism in the setting of right ventricular dysfunction. Algorithms Probability testing Recent recommendations for a diagnostic algorithm have been published by the PIOPED investigators; however, these recommendations do not reflect research using 64 slice MDCT. These investigators recommended:

 Low clinical probability. If negative D-dimer, PE is excluded. If positive D-dimer, obtain MDCT and based treatment on results.  Moderate clinical probability. If negative D-dimer, PE is excluded. However, the authors were not concerned that a negative MDCT with negative D-dimer in this setting has an 5% probability of being false. Presumably, the 5% error rate will fall as 64 slice MDCT is more commonly used. If positive D- dimer, obtain MDCT and based treatment on results.  High clinical probability. Proceed to MDCT. If positive, treat, if negative, additional tests are needed to exclude PE. Pulmonary embolism rule-out criteria The pulmonary embolism rule-out criteria (PERC) help assess people in whom pulmonary embolism is suspected, but unlikely. Unlike the Wells Score and Geneva score, which are clinical prediction rules intended to risk stratify patients with suspected PE, the PERC rule is designed to rule out risk of PE in patients when the physician has already stratified them into a low-risk category. People in this low risk category without any of these criteria may undergo no further diagnostic testing for PE:

Hypoxia — SaO2 <95%, unilateral leg swelling, hemoptysis, prior DVT or PE, recent surgery or trauma, age >50, hormone use, tachycardia. The rationale behind this decision is that further testing (specifically CT angiogram of the chest) may cause more harm (from radiation exposure and contrast dye) than the risk of PE. The PERC rule has a sensitivity of 97.4% and specificity of 21.9% with a false negative rate of 1.0% (16/1666).

Prevention Pulmonary embolism may be preventable in those with risk factors. For instance, people admitted to hospital may receive preventative medication and anti-thrombosis stockings to reduce the risk.[40] Following the completion of warfarin in those with prior PE, long term aspirin is useful to prevent re occurrence.

Treatment Anticoagulant therapy is the mainstay of treatment. Acutely, supportive treatments, such as oxygen or analgesia, may be required. People are often admitted to hospital in the early stages of treatment, and tend to remain under inpatient care until the INR has reached therapeutic levels. Increasingly, however, low-risk cases are managed at home in a fashion already common in the treatment of DVT. Evidence to support one approach versus the other is weak. Anticoagulation In most cases, anticoagulant therapy is the mainstay of treatment. Unfractionated heparin, low molecular weight heparin (LMWH), or fondaparinux is administered initially, while warfarin, acenocoumarol, or phenprocoumontherapy is commenced (this may take several days, usually while the patient is in the hospital). LMWH may reduce bleeding among people with pulmonary embolism as compared to heparin according to a systematic review ofrandomized controlled trials by the Cochrane Collaboration. The relative risk reduction was 40%. For people at similar risk to those in this study (2.0% had bleeding when not treated with low molecular weight heparin), this leads to an absolute risk reduction of 0.8%. 125 people must be treated for one to benefit. Warfarin therapy often requires frequent dose adjustment and monitoring of the international normalized ratio (INR). In PE, INRs between 2.0 and 3.0 are generally considered ideal. If another episode of PE occurs under warfarin treatment, the INR window may be increased to e.g. 2.5–3.5 (unless there are contraindications) or anticoagulation may be changed to a different anticoagulant e.g. LMWH. In patients with an underlying malignancy, therapy with a course of LMWH is favored over warfarin; it is continued for six months, at which point a decision should be reached as to whether ongoing treatment is required. Similarly, pregnant women are often maintained on low molecular weight heparin until at least 6 weeks after delivery to avoid the known teratogenic effects of warfarin, especially in the early stages of pregnancy. Warfarin therapy is usually continued for 3–6 months, or "lifelong" if there have been previous DVTs or PEs, or none of the usual risk factors is present. An abnormal D-dimer level at the end of treatment might signal the need for continued treatment among patients with a first unprovoked pulmonary embolus. For those with small PEs (known as subsegmental PEs) the effects of anticoagulation is unknown as it has not been properly studied as of 2014. Thrombolysis Massive PE causing hemodynamic instability (shock and/or hypotension, defined as a systolic blood pressure <90 mmHg or a pressure drop of 40 mmHg for >15 min if not caused by new-onset arrhythmia, hypovolemia or sepsis) is an indication for thrombolysis, the enzymatic destruction of the clot with medication. In this situation it is the best available treatment in those without contraindications and is supported by clinical guidelines. The use of thrombolysis in non-massive PEs is still debated. Some have found that the treatment decreases the risk of death and increases the risk of bleeding including intracranial hemorrhage. Others have found no decrease in the risk of death. Inferior vena cava filter

Used inferior vena cava filter. If anticoagulant therapy is contraindicated (e.g. shortly after a major operation), an inferior vena cava filter may be implanted to prevent new emboli from entering the pulmonary artery and combining with an existing blockage. It should be removed as soon as it becomes safe to start using anticoagulation. Surgery Surgical management of acute pulmonary embolism (pulmonary thrombectomy) is uncommon and has largely been abandoned because of poor long-term outcomes. However, recently, it has gone through a resurgence with the revision of the surgical technique and is thought to benefit certain people. Chronic pulmonary embolism leading to pulmonary hypertension(known as chronic thromboembolic hypertension) is treated with a surgical procedure known as a pulmonary thromboendarterectomy.